Apparatus and Process for the Automated Chemical Synthesis of Compounds

ABSTRACT

Provided is an process for the automated synthesis of at least one chemical compound including providing at least one substrate in at least one solvent in the at least one reaction container; automatically passing the at least one substrate through at least one first compartment of the at least one cartridge once or several times and collecting a formed substrate-reagent intermediate product in the at least one reaction container prior to passing the substrate-reagent intermediate product into a subsequent compartment; automatically passing the substrate-reagent intermediate product through at least one second compartment once or several times and collecting a formed reaction product prior to passing the reaction product into a subsequent compartment; automatically passing the reaction product through at least one third compartment for purifying the product once or several times and collecting a purified product in the at least one reaction container.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.16/065,940, filed Jun. 25, 2018, which is the United States nationalphase of International Application No. PCT/EP2017/050400 filed Jan. 10,2017, and claims priority to European Patent Application No. 16150878.3filed Jan. 12, 2016, the disclosures of which are hereby incorporated byreference in their entireties.

BACKGROUND OF THE INVENTION Field of the Invention

The present invention relates to an apparatus for the automated chemicalsynthesis of at least one compound, a process for the automated chemicalsynthesis of at least one compound and a cartridge.

Description of Related Art

In the last decades chemistry has evolved greatly and new technologiesand reactions are discovered faster than ever before. However the keyprocesses in organic chemistry have not changed for decades. Even today,many chemical compounds for basic research are still synthesized usinglaborious and resources inefficient processes, and in practice,synthetic chemistry still requires highly trained chemists. The processis time consuming since new reactions are setup following the carefulweighing of chemicals and the addition of solvents, and after completionof the reaction, a tedious workup and purification has to be conducted.

Slow reacting compounds cause further problems in organic synthesis andexcess reagents or harsh conditions are often required to push thereactions to higher conversions within a reasonable time frame, whichcan cause problems in the purification step. As a result, there is agreat demand for automation and simplification of such chemicalprocesses.

SUMMARY OF THE INVENTION

One object of the present invention is thus to address these limitationsof organic synthesis by enabling an unskilled user to rapidly synthesizeorganic compounds, in a fully automated manner that obviates the need toweigh and measure all but one of the reaction components, avoids the useof excess reagents, eliminates tedious reaction workups, and ultimatelyallows faster reaction times.

Another object is aimed mainly at aiding chemical research anddevelopment organizations, as it can greatly simplify the way in whichkey scaffolds are produced for research.

Yet another object is to provide a fully automated, flow chemistry-basedsynthesizer, which will utilize disposable polymer-supported reagentscartridges, for the production of key scaffolds, such as saturatedN-Heterocycles, which are key building blocks in many pharmaceutical andagricultural products. However, unlike their aromatic counterparts,there are limited strategies for the facile construction of substitutedsaturated N-Heterocycles by convergent, predictable methods.

Even the recently widely adopted SnAP methodology of choice (Vo et al.,Nature Chemistry, 2014, pages 310-314) has its limitations. It requiresthe user to handle highly toxic reagents and perform tedious workupprocedures. In addition, in the original solution-phase approach for thesynthesis of saturated N-heterocycles, several steps requiring userintervention are necessary, including imine formation, addition ofCu(OTf)₂, workup and purification. Each step is separated by a waitingperiod, which in total builds up to 12-24 h. If several compounds needto be produced, this multi-step methodology is rendered too timeconsuming. Therefore there is a great demand for novel, automatedmethods that enable the synthesis of these compounds and many others, ina simple, rapid and highly efficient manner.

These and other objects were solved by providing an apparatus withfeatures described herein and a process with features described herein.

Accordingly, an apparatus for the automated synthesis of at least onechemical compound, in particular for compounds comprising at least oneN-heterocyclic structure, is provided, wherein the apparatus comprises:

-   -   at least one cartridge comprising        -   at least one first compartment for providing at least one            first reagent for the chemical synthesis of the at least one            compound;        -   at least one second compartment for providing at least one            second reagent for the chemical synthesis of the at least            one compound, and        -   at least one third compartment for purifying the at least            one synthesized compound.    -   at least one reaction container for providing the compounds to        be fed into at least one of the compartments of the cartridge        and/or collecting the reaction product from at least one of the        compartments of the cartridge;    -   at least one solvent container for storing the solvent systems        used for at least one of the compartments of the cartridge;    -   optionally at least one waste container for collecting the waste        from at least one of the compartments of the cartridge, in        particular one waste container for all of the at least three        compartments;    -   at least two flow path selecting valves, wherein at least one        first valve selects the liquid source, in particular reaction        container or solvent reservoir, and the at least one second        valve directs the liquid to one of the compartments in the        cartridge, reaction container or optional waste container, and        -   at least one pump arranged downstream of the at least one            first valve and upstream of the at least one second valve,            i.e. the pump transfers or pumps the selected liquid from            the at least one first valve to the at least one second            valve.

Thus, an apparatus is provided that comprises separate vessels forstorage of the solvents and optional waste, and at least one separatecontainer for either the delivery of the substrate, storage of theintermediate products, or the final products. The present apparatusenables a passing of the substrate, intermediate product and/or reactionproduct from the vessels or container through the different compartmentsof the cartridge. The solution phase can be recycled multiple timesthrough each of the compartments comprising the physically separatedreagents to give improved reaction yields. In addition the flow througheach of the compartments of the cartridge can be independentlycontrolled. That allows recycling through a specific compartment of thecartridge and thus contact with the respective reagent for as long asrequired. This offers a significant advantage over a single pass througheach compartment since the flow rate through each compartment and numberof cycle times can be controlled to optimize the yield, and enableschemical reactions that would not be possible using a single passmethod.

The cartridge that is provided in the present apparatus is separatedinto several compartments, wherein the cartridge comprises at least onecompartment for each of the three steps: first reagent compartment,second reagent compartment and purification compartment. In the presentcartridge all essential components required for the chemical synthesisare contained in the compartments of the cartridge and which allows afully automated synthesis.

It is possible to provide the substrate neat or in a differentconcentration (such as 0.1-1.0 mmol) which reacts with the reagent inthe reagent compartment by forming a substrate-reagent intermediateproduct, which is released from the solid support of the at least onefirst reagent compartment. Furthermore, a range of alternativeimmobilized reagents can be used enabling the synthesis of a broad rangeof different compounds. Further, the first reaction product can bepassed through the second reagent compartment (which comprises forexample a non-immobilized reactant in catalytic or stoichiometricamounts) to trigger a transformation.

In an embodiment the cartridge comprises at least one further fourthcompartment for removing any (non-reacted) reagent material, such as anycatalyst material, from the reaction mixture.

It is in general to be understood that the there is no specificarrangement order of the compartments. The order rather depends on thespecific chemical reaction requirements. Thus, in one embodiment theorder may be first reagent compartment, second reagent compartment,purification compartment. In another embodiment the order may be firstreagent compartment, purification compartment, and second reagentcompartment. There also may be more than one purification compartment.In this case the order may be first reagent compartment, firstpurification compartment, second reagent compartment, and secondpurification compartment. Any combination of the compartments ispossible.

The compartments of the cartridge may preferably have a cylindricalshape with different lengths for example a length in a range between 50and 150 mm, preferably between 70 and 100 mm, and a diameter between 5and 15 mm, preferably between 8 and 10 mm. The cartridge andcompartments may be made of plastic material, respectively. Furthermore,cartridge and compartments may be made in one piece.

The compartments may be spatially separated from each other and/orarranged next to each other, for example parallel or in line.

It also preferred that each of the compartments comprises at least oneinlet and one outlet. Thus, each compartment is connected via inlet andoutlet to a reaction container and/or a solvent reservoir.

Thus, the cartridge with the three or four compartments is coupled to atleast one reaction container storing the starting material and/or thereaction products of each compartment and at least one solvent reservoirfor storing the solvent required for the different reaction sequences inthe compartments of the cartridge and optionally at least one wastecontainer.

It is however also conceivable that at least one reaction containerand/or at least one solvent reservoir is assigned to each single one ofthe compartments. The number of reaction containers and/or solventreservoirs can thus vary and depend on the specific processrequirements.

In a preferred embodiment of the present apparatus each of thecompartments of the cartridge comprises

-   -   at least one inlet that is operatively linked to the at least        one second valve that directs the liquid to one of the        compartments in the cartridge, and    -   at least one outlet that is operatively linked to the at least        one reaction container and optionally at least one waste        container.

In an embodiment of the present apparatus the at least one cartridgecomprises

-   -   at least one first compartment A comprising the first reagent as        at least one immobilized reagent;    -   at least one second compartment B comprising at least one        catalyst as the second reagent;    -   at least one third compartment C comprising at least one        scavenging matrix for removing the at least one catalyst from        the reaction mixture, and    -   at least one fourth compartment D comprising at least one ion        exchange support for purifying the reaction product,

It is furthermore preferred, if the at least one third compartment C ofthe at least one cartridge comprises at least one scavenging matrix forremoving the at least one catalyst selected from a group comprisingpolymer-supported thiourea, polymer-supported trisamine andsilica-supported trisamine.

It also preferred, if the at least one fourth compartment D of the atleast one cartridge comprises an ion exchange resin or a silicasupported ion exchange such as solid supported sulfonic acid, forpurifying the reaction product.

In a preferred embodiment the cartridge used in the present apparatusfor the chemical synthesis of at least one compound comprising at leastone N-heterocyclic structure, wherein said cartridge comprises thefollowing compartments at least one of the followings:

-   -   at least one first compartment A        -   comprising the first reagent as at least one of an            immobilized Sn-containing reagent (SnAP reagent) of the            general formulae (Ia)

R¹R²R³Sn—CH₂—X—(CR⁴R⁵)_(n)—(CR⁶R⁷)_(m)—N═Y-carrier

-   -   or of the general formulae (Ib)

R¹R²R³Sn—CHXR¹⁰—(CR⁴R⁵)_(n)—(CR⁶R⁷)_(m)—N═Y-carrier

-   -   wherein        -   R¹, R², R³, R¹⁰ are selected from a group comprising alkyl,            wherein R¹, R², R³ can be the same or different;        -   X is selected from a group comprising O, protected N, S;        -   R⁴, R⁵, R⁶, R⁷ are selected from a group comprising H,            alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, wherein R⁴,            R⁵, R⁶, R⁷ can be the same or different; and/or        -   at least one of R⁴, R⁵ and at least one of R⁶, R⁷ together            form an alkyl or aryl ring system, or        -   at least two of R⁴ and R⁵ or at least two of R⁶, R⁷ together            form a alkyl or aryl spirocyclic ring system,        -   which can be interrupted by one or multiple oxygen atoms,            sulphur atoms, substituted and/or unsubstituted nitrogen            atoms and/or by one or multiple groups of the type —C(O)O—,            —OC(O)—, —C(O)—, —NHC(O)O—, —OC(O)NH— and/or —OC(O)O,        -   n, m=1-6, preferably 1-5, 1, 2, 3, 4, 5,        -   Y═P(R¹¹)₂, wherein R¹¹ can be at least one alkyl or aryl,        -   carrier is a polymer or a silica compound, such as a silica            gel,        -   wherein the at least of Sn-containing reagent of general            formulae (Ia) or (Ib) is able to react with at least one            aldehyde of the general formulae (IIa)

R⁸—CHO

-   -   or at least one ketone of the general formulae (IIb)

R⁸R⁹CO

-   -   -   wherein R⁸ and R⁹ are selected from a group comprising            alkyl, alkenyl, cycloalkyl, cycloalkenyl, —COOR¹² (R¹² being            alkyl), aryl, heteroaryl, which are in each case            non-substituted or substituted; or where R⁸ and R⁹ are            joined to form an alkyl or aryl ring system, in particular a            C₄-C₈ alkyl ring,        -   which can be interrupted by one or multiple oxygen atoms,            sulphur atoms, substituted and/or unsubstituted nitrogen            atoms and/or by one or multiple groups of the type —C(O)O—,            —OC(O)—, —C(O)—, —NHC(O)O—, —OC(O)NH— and/or —OC(O)O,        -   to form at least one imine or ketimine;

    -   at least one second compartment B        -   comprising the second reagent as at least one catalyst for            cyclization of the at least one imine or the at least one            ketimine leaving the first compartment A to at least one            N-heterocyclic compound of the general structure (IIIa)

-   -   -   or of the general structure (IIIb)

-   -   -   or of the general structure (IIIc)

-   -   -   wherein R⁴-R⁹ have the above meanings        -   wherein the at least one cyclization catalyst is selected            from a group comprising a transition metal salt, such as a            copper salt or a Scandium salt,

    -   at least one third compartment C        -   comprising at least one scavenging matrix for removing the            at least one cyclization catalyst from the reaction mixture            comprising the N-heterocyclic compound leaving the at least            one second compartment B,

    -   at least one fourth compartment D        -   comprising at least one ion exchange support for purifying            the N-heterocyclic reaction product.

Thus, the cartridge provides all essential components required for thesynthesis of N-heterocycles. The immobilized reagents in thecompartments of the cassette or cartridge allow a fully automatedsynthesis. Furthermore, a range of alternative immobilized reagents canbe used. In particular, many different immobilized SnAP reagents can beused to fill the preferably disposable cassettes or cartridges, enablinggeneration of a broad range of different saturated N-heterocycles.

In an embodiment of the present cartridge the at least one firstcompartment A comprises

-   -   at least one of a polymer immobilized Sn-containing reagent of        the general formulae (Ia)

R¹R²R³Sn—CH₂—X—(CR⁴R⁵)_(n)—(CR⁶R⁷)_(m)—N═Y-polymer

-   -   or of the general formulae (Ib)

R¹R²R³Sn—CHXR¹⁰—(CR⁴R⁵)_(n)—(CR⁶R⁷)_(m)—N═Y-polymer

-   -   wherein        -   R¹, R², R³, R¹⁰ are selected from a group comprising C₁-C₁₀            alkyl, preferably C₁-C₆ alkyl, in particular preferably C₄            alkyl such as butyl, tert-butyl, iso-butyl, wherein R¹, R²,            R³ can be the same or different;        -   X is selected from a group comprising 0, protected N, S;        -   R⁴, R⁵, R⁶, R⁷ are selected from a group comprising H,            C₁-C₂₀ alkyl, C₅-C₁₀ cycloalkyl, C₂-C₂₀ alkenyl, C₅-C₁₀            cycloalkenyl, C₆-C₁₂ aryl, wherein R⁴, R⁵, R⁶, R⁷ can be the            same or different; and/or        -   at least one of R⁴, R⁵ and at least one of R⁶, R⁷ together            form a 5 to 12 membered alkyl or aryl ring system, in            particular a 6 membered alkyl or aryl ring system, such as            C6 aryl ring, or        -   at least two of R⁴ and R⁵ or at least two of R⁶, R⁷ together            form a 4-7 membered alkyl or (hetero-)aryl spirocyclic ring            systems;        -   which can be interrupted by one or multiple oxygen atoms,            sulphur atoms, substituted and/or unsubstituted nitrogen            atoms and/or by one or multiple groups of the type —C(O)O—,            —OC(O)—, —C(O)—, —NHC(O)O—, —OC(O)NH— and/or —OC(O)O,            -   n, m=1, 2, 3, 4, 5,            -   Y═P(R¹¹)₂, wherein R¹¹ is aryl, in particular Ph;            -   carrier is polystyrene,        -   wherein the at least of Sn-containing reagent of general            formulae (Ia) or (Ib) is able to react with at least one            aldehyde of the general formulae (IIa)

R⁸—CHO

-   -   or at least one ketone of the general formulae (IIb)

R⁸R⁹CO

-   -   -   wherein R⁸ and R⁹ are selected from a group comprising            C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₅-C₁₀ cycloalkyl, C₅-C₁₀            cycloalkenyl, —COOR¹² (R¹² being C₁-C₁₀ alkyl), C₆-C₁₂ aryl,            or where R⁸ and R⁹ are joined to form an C₅-C₁₂ alkyl or            C₆-C₁₂ aryl ring system, in particular a C6 aryl ring        -   which can be interrupted by one or multiple oxygen atoms,            sulphur atoms, substituted and/or unsubstituted nitrogen            atoms and/or by one or multiple groups of the type —C(O)O—,            —OC(O)—, —C(O)—, —NHC(O)O—, —OC(O)NH— and/or —OC(O)O,        -   to form at least one imine or ketimine.

The moieties R⁴, R⁵, R⁶, R⁷ can be selected from a group comprising H,C₁-C₁₂ alkyl, C₅-C₇ cycloalkyl, C₂-C₁₂ alkenyl, C₆-C₁₂ aryl orheteroaryl, in particular methyl, ethyl, propyl, phenyl (unsubstitutedor substituted with F, Cl, CF₃), pyridine.

Preferred Examples for Sn-containing reagent of general formulae (Ia) or(Ib) are

In a more specific embodiment the following Sn-containing reagents areprovided:

In another variant of the present cartridge the at least one secondcompartment B comprises at least one catalyst selected from a groupcomprising Cu and Sc salts (such as ScCl₃), in particular Cu(Z)₂ whereinZ is selected from a group containing OTf, Cl, Br, SO₄ ²⁻, in particularCu(OTf)₂.

In yet another variant of the present cartridge the at least one thirdcompartment C comprises at least one scavenging matrix for removing theat least one cyclization catalyst selected from a group comprisingpolymer-supported thiourea, polymer-supported trisamine andsilica-supported trisamine.

In still another variant of the present cartridge the at least onefourth compartment D comprises an ion exchange resin or a silicasupported ion exchange such as solid supported sulfonic acid, forpurifying the N-heterocyclic reaction product.

The cartridge of the present apparatus is preferably placed in acartridge holder that may be coupled to the synthesis apparatus.

The cartridge holder may comprise two parts wherein at least one part ofthe cartridge holder is heated and the other part of the cartridgeholder is not heated. The heated section of the cartridge holdercomprises also at least one heating unit and is made of a suitablemetal, such as aluminum. The non-heated section of the cartridge holderis kept at room temperature and is preferably made of plastics such aspolypropylene/polycarbonate. Such asymmetrical arrangement of heated andnon-heated section (which may be also color coded) may also prevent anerroneous insertion of the cartridge into the cartridge holder. This isimportant since in one embodiment only the three compartments A-C shouldbe heated whereas the fourth compartment D should be kept at roomtemperature.

Accordingly, in an embodiment the heated section of the cartridge holderis adapted to house any of the compartments comprising the first reagentand the second reagent, such as a catalyst, and the non-heated sectionof the cartridge holder is adapted to house the purificationcompartment. In a specific embodiment the cartridge holder is adapted tohouse the compartments A, B and C and the non-heated section of thecartridge holder is adapted to house the compartment D.

As stated above, the present apparatus is coupled to at least onereaction container for providing the compounds to be fed into at leastone of the compartments of the cartridge, in particular into at leastone of the compartments A-D of the cartridge and/or collecting thereaction product from at least one of the compartments, in particular ofthe compartments A-D of the cartridge; in particular one reactioncontainer for all of the at least four compartments. Thus, the reactioncontainer(s) used in the present apparatus and the below describedprocess can be the same or different. For example one reaction containeris used repeatedly for all educts and products. It is also possible thatone reaction container is used for educts/products from eachcompartment.

The reaction container may provide the starting material such asaldehyde/ketone and receive the product. It also acts as reactioncontainer where the reaction liquid is contained. Since the volume ofthe flow path is smaller than the volume of the solvent used in thereaction the container acts much like a buffer or temporary storage.

The reaction container can be defined as any vessel capable ofcontaining or storing the reactants, intermediates or products from thecompartments, for example, as vial, a tubing loop, or a chip-basedreactor. The reaction container is also capable of being heated orirradiated with light.

As stated above. the present apparatus is also coupled to at least onesolvent reservoir for storing the solvent systems used for at least oneof the compartments of the cartridge; in particular solvent reservoirsfor all of the at least four compartments A-D. Several solventreservoirs may be used for the whole apparatus that are not designatedto one specific compartment but are used for all compartments of theapparatus.

The present apparatus may further be coupled to at least one wastecontainer for collecting the waste from at least one of the compartmentsof the cartridge, in particular one waste container for all of the atleast three or four compartments. It is however also conceivable toprovide one separate waste container for each of the at least three orfour compartments.

As also stated above, the present apparatus comprises at least two flowpath selecting valves, wherein at least one first valve selects theliquid source, in particular reaction container or solvent reservoir,and the other second valve directs the liquid to one of thecompartments, reaction container or waste container. The valves arecommercially available components consisting for example of a flow pathselecting Teflon valve with attached stepper motors.

The present apparatus comprises also at least one pump for all liquidsused in the synthesis process, wherein the at least one pump is arrangeddownstream of the at least one first valve and upstream of the othersecond valve. Thus, the at least one pump connects the at least two flowpath selecting valves. A commercially available solenoid pump may beused as a pump.

The present apparatus also may comprise at least one stirring unit.Specifically, each reaction container may comprise at least one stirringmeans. The stirring means may for example consists of four smallinductive coils. These are magnetized in a circular fashion to propel asmall magnetic stir bar in the reaction container.

In yet another variant the present apparatus comprises at least onemicrocontroller for operating/controlling the at least two flow pathselecting valves, the at least one pump, the at least one heating unitand the at least one stirring unit.

In one further embodiment the apparatus comprises at least onetouchscreen. The touchscreen offers a simple, intuitive user interfaceand sends all commands to the microcontroller to be processed. Theapparatus could also be controlled by external interface via RS-232,RS-485 or USB.

It is also possible that the apparatus may also contain furtherelectrical components like a RFID reader for automatic recognition ofthe inserted cartridges/cartridges and connected compartments.

The present apparatus is used for a process for the automated synthesisof chemical compounds comprising the steps

-   -   providing at least one substrate in at least one solvent in the        at least one reaction container;    -   automatically passing the at least one substrate through the at        least one first reagent compartment once or several times and        collecting the formed substrate-reagent intermediate product        (i.e. formed when passing the at least one first reagent        compartment) in the at least one reaction container prior to        passing the substrate-reagent intermediate product into the        subsequent compartments;    -   automatically passing the substrate-reagent intermediate product        through the at least one second reagent compartment once or        several times and collecting the formed reaction product (i.e.        formed when passing the at least one second reagent compartment)        in the at least one reaction container prior to passing the        reaction product into the subsequent compartments;    -   automatically passing the reaction product through the at least        one third compartment for purifying the product once or several        times and collecting the purified product in the at least one        reaction container.

It is to be understood that the order of the process step may vary. Forexample, it is possible that the substrate-reagent intermediate leavingthe first compartment comprising the first reagent is passed through thepurification compartment and only subsequently through the compartmentcomprising the second reagent followed by another purification step. Anycombination is possible and is chosen according to the specific reactionrequirements.

In an embodiment of the present process for the automated synthesis of achemical compound the process comprises the steps:

-   -   providing at least one substrate in at least one solvent in the        at least one reaction container;    -   automatically passing the at least one substrate once or several        times through at least one first compartment A comprising the        first reagent as at least one immobilized reagent and collecting        the formed substrate-reagent intermediate product in the at        least one reaction container prior to passing the        substrate-reagent intermediate product into a subsequent        compartment B;    -   automatically passing the substrate-reagent intermediate product        through at least one second compartment B comprising at least        one catalyst as the second reagent once or several times and        collecting the formed reaction product in the at least one        reaction container prior to passing the reaction product into a        subsequent compartment C;    -   automatically passing the reaction product formed in compartment        C through at least one third compartment C comprising at least        one scavenging matrix for removing the at least one catalyst        from the reaction mixture and collecting the formed reaction        product in the at least one reaction container prior to passing        the reaction product into a subsequent compartment D; and    -   automatically passing the reaction product obtained in        compartment C through at least one fourth compartment D        comprising at least one ion exchange support for purifying the        reaction product once or several times and collecting the        purified product in the at least one reaction container.

In an embodiment the process for the automated synthesis of compoundscomprising at least one N-heterocyclic structure comprises the steps:

-   -   providing at least one aldehyde of the general formulae (IIa)        R⁸—CHO or at least one ketone of the general formulae (IIb)        R⁸R⁹CO, wherein R⁸ and R⁹ have the above meanings, in at least        one organic solvent in at least one reaction container;    -   passing said aldehyde or ketone solution through the at least        one compartment A comprising the at least one immobilized        Sn-containing reagent of general formulae (Ia) or general        formulae (Ib); and collecting the imine or ketimine solution        formed when passing through compartment A in at least one        reaction container;    -   passing said imine or ketimine solution through the at least one        second compartment B comprising the at least one cyclization        catalyst and collecting the at least one N-heterocyclic compound        of the general formulae (IIIa), (IIIb) or (IIIc) formed when        passing through compartment B in at least one reaction        container;    -   passing said N-heterocyclic compound of the general formulae        (IIIa), (IIIb) or (IIIc) through the at least one third        compartment C comprising the at least one cyclization catalyst        scavenging matrix and collecting the cyclized catalyst free        N-heterocyclic compound of the general formulae (IIIa), (IIIb)        or (IIIc) in at least one reaction container;    -   loading the at least one fourth compartment D comprising at        least one ion exchange support with the cyclized catalyst free        N-heterocyclic compound of the general formulae (IIIa), (IIIb)        or (IIIc), washing the loaded ion exchange support with an        appropriate solvent system; eluting the N-heterocyclic reaction        product from the ion exchange support using an appropriate        solvent system and collecting the eluted N-heterocyclic reaction        product in at least one reaction container.

The solutions are passed through compartments A-C by pumping in circularflow for 5 to 120 min, preferably for 10 to 45 min, most preferably for20 to 30 min at a temperature between 40 and 100° C., preferably between50 and 80° C., most preferably between 60 and 70° C. In general theapplied temperature of the heating unit should not raise more than 20°C. above the boiling point of the solvent used in the reaction.

In case of compartment D the solutions are passed through by pumping incircular flow for 5 to 60 min, preferably for 10 to 45 min, mostpreferably for 20 to 30 min at room temperature.

Within the meaning of the present invention circular flow means thatliquid is pumped from reaction container to flow path selecting valve Ato pump to flow path selecting valve B through one of the compartmentsof the cartridge into the reaction container.

The maximum flow rate for the used pump is given to be 24 ml/min forwater from the manufacturer. In case of the used solvents a maximum flowrate of 10 ml/min is possible. The flow rate is adjusted such that noback pressure is experienced.

The different reaction steps in compartments A-D may require specificsolvents. For example, the imine/ketimine formation in compartment A iscarried out in CH₂Cl₂. The cyclization in Compartment B uses inparticular acetonitrile, 2,6-lutidine, CH₂Cl₂ or HFIP as organicsolvent. The scavenging step in compartment C uses preferably CH₂Cl₂,C₂H₄Cl₂, or MeOH.

In compartment D the loaded support is preferably washed with an organicsolvent such CH₂Cl₂ and MeOH; wherein the N-heterocyclic reactionproduct is eluted from the resin using preferably a mixture of an aminein MeOH or 0.1M NH₃ in MeOH.

In general the type of solvent or solvent mixture is determined by theeducts and products and can thus vary.

In a variant of the present process the reaction product is eluted fromthe at least one purifying compartment after the cartridge is removed bythe user from the apparatus. In particular the at least one fourthcompartment D with loaded N-heterocyclic reaction product is removed bythe user from the apparatus and the N-heterocyclic product is elutedseparately at any time using the appropriate solvent system.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is described in more detail by means of the followingexamples with reference to the Figures. It shows:

FIG. 1 an embodiment of an apparatus according to an embodiment of thepresent invention;

FIG. 2A a scheme of electrical components of an apparatus for automatedsynthesis according to an embodiment of the present invention;

FIG. 2B a general flow scheme for liquids in an apparatus according toone embodiment of the present invention;

FIG. 3A an embodiment of a cartridge according to the invention;

FIG. 3B a scheme of components of an apparatus according to anembodiment of the present invention;

FIG. 4 a further flow scheme for liquids in an apparatus and a cartridgeaccording to another embodiment of the present invention; and

FIG. 5 an embodiment of a cartridge holder.

DESCRIPTION OF THE INVENTION

In FIG. 1 an embodiment of the automatic synthesizer or apparatus isdepicted. The apparatus comprises a Touchscreen 1, On/Off Button 2, twoFlow path selecting valves 3 a,b, a Pump 4, a heating unit 5 preferablymade of Aluminum, a single cartridge 6 inserted in the section of aheated cartridge holder 7 a, the non-heated section of the cartridgeholder 7 b.

FIG. 2A shows a general scheme of the different electrical componentsrequired in the present apparatus for automated synthesis ofN-heterocyclic structures. FIG. 3B shows a general scheme of componentsof an embodiment of the apparatus.

A common 12V power supply feeds power to the central microcontrollerboard. It handles the whole program and directs the necessary power tothe individual components. The touchscreen offers a simple, intuitiveuser interface and sends all commands to the microcontroller to beprocessed. The apparatus could also be controlled by an externalinterface via RS-232, RS-485 or USB. From the user commands obtained,the microcontroller operates the two flow path selecting valves, pump,heating unit and a stirring unit. The valves are commercial availablecomponents consisting of a flow path selecting Teflon valve withattached stepper motors. A commercial available pump is used here, forexample a solenoid pump. The heating unit is composed of aluminum withfour heating capsules inside. A temperature probe measures the currenttemperature and the microcontroller adjusts the heating power to thetemperature set by the user. The stirring unit consists of four smallinductive coils. These are magnetized in a circular fashion to propel asmall magnetic stir bar in the reaction container. The machine may alsocontain further electrical components like a RFID reader for automaticrecognition of the inserted cartridge.

The scheme depict in FIG. 2B provides an overview of a general flowscheme for liquids in the automated synthesizer. The automatedsynthesizer uses two 8-port flow path selecting valves and a pump tohandle all liquids during the process. One valve has the task ofselecting the source of liquid for the pump (solvent reservoirs/reactioncontainer). The other valve chooses the destination of the liquid orreagent (Waste Container/Reagent Compartments/Reaction Container).

The basic concept of the present invention is explained by means of theembodiment of a cartridge shown in FIG. 3A. In the basic concept thereis one cartridge which is separated into several, at least threecompartments. The cartridge contains at least one compartment for eachof the three steps (Reagent compartment, second reagent compartment,Purification compartment).

The substrate can be delivered neat or a substrate concentration rangeof between 0.1 and 1.0 mmol can be used. The machine is capable ofdissolving the substrate given to adjust it to the requiredconcentration. The substrate reacts with the reagent in the reagentcompartment and the resulting reagent is released from the solidsupport. Therefore only the desired amount of reagent is releasedavoiding any contamination with excess reagent. According to the examplein FIG. 3A 0.2 mmol substrate reacts in the reagent compartmentcontaining 1.0 mmol reagent on a polymer support. Only 0.2 mmol is thenreleased as [substrate-reagent]intermediate product. 0.8 mmol reagentremains on polymer support in the reagent compartment.

The substrate-reagent intermediate product is then fed into a secondreagent (a catalyst or stoichiometric reagent) compartment and thedesired product is formed and collected in a reaction container. Theproduct containing impurities is then fed into the purificationcompartment containing a commercial purification resin/matrix and thepurified product is collected.

The flow scheme of FIG. 4 shows an embodiment of the invention. Here thecartridge comprises four compartments A-D. The inlets of each of thecompartments are coupled to one flow path selecting valve (left valve 3b). Said left valve 3 b selects the flow of the liquid or substrate intoone of the four compartments. Outlet 1 of the left valve 3 b is coupledto compartment A, outlet 2 is coupled to the inlet of compartment B,outlet 3 is coupled to the inlet of compartment C and outlet 4 iscoupled to the inlet of compartment D. The outlets of each of thecompartments A-D are connected to a reaction container which contains astirring element. The other valve (right valve 3 a) selects the sourceof liquid for the pump (solvent reservoirs/reaction container).

The cartridge holder shown in FIG. 5 comprises two sections: a heatedmetal section 7 a and a non-heated section 7 b made of polypropylene.The cartridge 6 comprising the four compartments A-D is inserted intothe holder such that compartments A-C are placed in the heated section 7a and compartment D is placed in the non-heated section 7 b.

Example Procedure:

a) Step A: Imine/Ketimine Formation

To start the process a user has to insert a new cartridge into thecartridge holder and provide the aldehyde or ketone (0.1 to 0.5 mmol) inthe defined reaction container containing a small magnetic stir bar intothe holder in the machine. The synthesizer adds solvent (4 mL DCM orDCE) to the starting material from the solvent reservoir by flowing itthrough compartment A of the cartridge containing 1.5 mmol of theimmobilized SnAP reagent.

Afterwards the solution is pumped through compartment A via circularflow for 15 min at 60° C. to form the imine. The residual reagent incompartment A is then washed out with 4 mL DCM or DCE from the solventreservoir to the reaction container.

b) Step B: Cyclization

To this solution 2 mL HFIP and 2,6-lutidine (0.5 mmol) are added fromthe solvent reservoirs through compartment B of the cartridge,containing 200 mg Cu(OTf)₂, into the reaction container. The mixture isthen pumped through compartment B via circular flow for 30 min at 60° C.while stirring the reaction container. The residual reagent incompartment B is then washed out with 4 mL DCM or DCE from the solventreservoir to the reaction container.

Examples of cyclization products include

c) Step C: Scavenging

The product containing solution in the reaction container is then pumpedthrough the compartment C containing 500 mg Cu scavenging resin for 10min at 60° C. via circular flow to remove copper compounds in themixture. The residual reagent in compartment C is then washed out with 4mL DCM or DCE from the solvent reservoir to the reaction container.

d) Step D: Product Purification

For purification of the product the mixture is pumped through theproduct catch compartment D, containing 1 g of ion exchange resin, for10 min at room temperature to catch all product on the resin. The solidsupport is then washed with 10 mL of MeOH from the solvent reservoir towash out all impurities.

The waste solution in the reaction container is then pumped into thewaste and the container itself is washed with DCM and MeOH from thesolvent reservoir which is then pumped into the waste as well.

In the last step the product on the resin is eluted from compartment Dusing a solution of NH₃ in MeOH (5 mL, 0.1 M) from the solventreservoirs into the reaction container.

Alternatively the product containing cartridge can be removed by theuser and compartment D purged with NH₃ in MeOH to release the productmanually.

The following table summarizes the process step-by-step. The SnAPprocess is run in a single flask system using 0.5 mmol aldehyde as asubstrate. The numbers for valve A and B refer to the port number thatthe rotary valve is set to. The pump speed value refers to an arbitraryset value (1-20), which reflects speed values between 0% and 100% of themaximum speed.

The concentration refers to the concentration of the aldehyde or itsconversion products. The concentration decreases over time since a smallvolume of solvent is added in some steps to wash the compartments.

valve valve pump Add magnetic Conc. B A speed solvent time stirrerheater Remarks (M) 1 1 8  4 mL off 60° C. add 0.125 solvent/dissolvealdehyde 1 2 10 — 10 min off 60° C. imine or ketimine 0.125 formation 11 8  4 mL off 60° C. wash 0.042 compartment A 2 3 8  2 mL on, speed = 1360° C. add HFIP and 0.036 ligand 2 2 10 — 30 min on, speed = 13 60° C.cyclization by 0.036 flow through compartment B 2 4 8  4 mL on, speed =13 60° C. wash 0.023 compartment B 3 2 10 — 10 min off 60° C. metalremoving 0.023 in compartment C 3 4 8  4 mL off 60° C. wash 0.019compartment C 4 2 10 —  5 min off rt product catch on 0.019 solidsupport in compartment D 4 5 8 10 mL off rt washing away N/A impurity ofcompartment D

1. A process for the automated synthesis of chemical compounds,comprising: providing an apparatus comprising: (a) at least one solventcontainer for storing solvent system(s) used for at least onecompartment of at least one cartridge, the at least one solventcontainer comprising at least one solvent reservoir, the at least onesolvent reservoir having an inlet and an outlet, (b) at least onereaction container for providing compound(s) to be fed into at least oneof the compartments of the at least one cartridge and/or collectingreaction product(s) from at least one of the compartments of the atleast one cartridge, the at least one reaction container having an inletand an outlet; (c) at least one first valve for selecting a liquidsource from the at least one solvent reservoir or the at least onereaction container, the at least one first valve having an inletconnected to the outlet of the at least one solvent reservoir and theoutlet of the at least one reaction container, and an outlet connectedto a pump inlet; (d) at least one pump comprising a first pumpcomprising the pump inlet for receiving liquid from the outlet of thefirst valve and a pump outlet connected to an inlet of at least onesecond valve for directing the liquid received from the at least onefirst valve to the at least one second valve either directly or throughoptional pump(s) of the at least one pump; (e) the at least one secondvalve for directing the liquid received from the at least one pump to aninlet of at least one compartment of the at least one cartridge or theinlet of the at least one reaction container, the at least one secondvalve having the inlet for receiving the liquid from the at least onepump, and an outlet connected to the inlet of the at least onecompartment of the at least one cartridge and the inlet of the at leastone reaction container; and (f) at least one cartridge comprising: (i)at least one first compartment for providing at least one first reagentfor the chemical synthesis of the at least one compound, the at leastone first compartment having the inlet connected to the outlet of the atleast one second valve, and an outlet connected to the at least onereaction container for passing a formed substrate-reagent intermediateproduct into the at least one reaction container; (ii) at least onesecond compartment for providing at least one second reagent for thechemical synthesis of the at least one compound, the at least one secondcompartment having an inlet for receiving the substrate-reagentintermediate product from the outlet of the at least one reactioncontainer, and an outlet connected to the inlet of the at least onereaction container for passing the formed reaction product into the atleast one reaction container, and (iii) at least one third compartmentfor purifying the at least one synthesized compound, the at least onethird compartment having an inlet connected to the outlet of thereaction container for receiving the formed reaction product from theoutlet of the first reaction container, and an outlet connected to theinlet of the at least one reaction container for passing the purifiedproduct into the at least one reaction container, providing at least onesubstrate in at least one solvent in the at least one reactioncontainer; automatically passing the at least one substrate through atleast one first compartment of the at least one cartridge once orseveral times and collecting a formed substrate-reagent intermediateproduct in the at least one reaction container prior to passing thesubstrate-reagent intermediate product into a subsequent compartment;automatically passing the substrate-reagent intermediate product throughat least one second compartment once or several times and collecting aformed reaction product formed in the at least one reaction containerprior to passing the reaction product into a subsequent compartment;automatically passing the reaction product through at least one thirdcompartment for purifying the product once or several times andcollecting a purified product in the at least one reaction container. 2.The process according to claim 1 for the automated synthesis of achemical compound comprising: providing at least one substrate in atleast one solvent in the at least one reaction container; automaticallypassing the at least one substrate once or several times through the atleast one first compartment comprising a first reagent as at least oneimmobilized reagent and collecting the formed substrate-reagentintermediate product in the at least one reaction container prior topassing the substrate-reagent intermediate product into a subsequentcompartment; automatically passing the substrate-reagent intermediateproduct through at least one second compartment comprising at least onecatalyst as the second reagent once or several times and collecting theformed reaction product in the at least one reaction container prior topassing the reaction product into a subsequent compartment;automatically passing the reaction product formed in the at least onesecond compartment through at least one third compartment comprising atleast one scavenging matrix for removing the at least one catalyst fromthe reaction mixture and collecting the formed reaction product in theat least one reaction container prior to passing the reaction productinto a subsequent compartment; and automatically passing the reactionproduct obtained in the at least one third compartment through at leastone fourth compartment comprising at least one ion exchange support forpurifying the reaction product once or several times and collecting thepurified product in the at least one reaction container.
 3. The processaccording to claim 1 for the automated synthesis of a chemical compoundcomprising at least one N-heterocyclic structure comprising: providingat least one aldehyde of the general formulae (IIa) R⁸—CHO or at leastone ketone of the general formulae (IIb) R⁸R⁹CO, wherein R⁸ and R⁹ areselected from a group comprising alkyl, alkenyl, cycloalkyl,cycloalkenyl, —COOR¹² (R¹² being alkyl), aryl, heteroaryl, which are ineach case non-substituted or substituted; or where R⁸ and R⁹ are joinedto form an alkyl ring system, which can be interrupted by one ormultiple oxygen atoms, sulphur atoms, substituted and/or unsubstitutednitrogen atoms and/or by one or multiple groups of the type —C(O)O—,—OC(O)—, —C(O)—, —NHC(O)O—, —OC(O)NH— and/or —OC(O)O, to form at leastone imine or ketimine, in at least one organic solvent in the at leastone reaction container; passing said aldehyde or ketone solution throughthe at least one first compartment comprising at least one immobilizedSn-containing reagent of general formulae (Ia) or general formulae (Ib),and collecting an imine or ketimine solution formed when passing thesubstrate through the at least one first compartment and into at leastone reaction container, wherein general formulae (Ia) isR¹R²R³Sn—CH₂—X—(CR⁴R⁵)_(n)—(CR⁶R⁷)_(m)—NY-carrier and general formulae(Ib) is R¹R²R³Sn—CHXR¹⁰—(CR⁴R⁵)_(n)—(CR⁶R⁷)_(m)—N═Y-carrier, wherein R¹,R², R³, R¹⁰ are selected from a group comprising alkyl, wherein R¹, R²,R³ can be the same or different; X is selected from a group comprisingO, protected N, S; R⁴, R⁵, R⁶, R⁷ are selected from a group comprisingH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, wherein R⁴, R⁵, R⁶,R⁷ can be the same or different; and/or at least one of R⁴, R⁵ and atleast one of R⁶, R⁷ together form an alkyl or (hetero-) aryl ringsystem, or at least two of R⁴ and R⁵ or at least two of R⁶, R⁷ togetherform a alkyl or aryl spirocyclic ring system, which can be interruptedby one or multiple oxygen atoms, sulphur atoms, substituted and/orunsubstituted nitrogen atoms and/or by one or multiple groups of thetype —C(O)O—, —OC(O)—, —C(O)—, —NHC(O)O—, —OC(O)NH— and/or —OC(O)O, n,m=1-6, Y═P(R¹¹)₂, wherein R¹¹ can be at least one alkyl or aryl, carrieris a polymer or a silica compound; passing said imine or ketiminesolution through the at least one second compartment comprising at leastone cyclization catalyst and collecting at least one N-heterocycliccompound of the general formulae (IIIa); (IIIb) or (IIIc) formed whenpassing the imine or ketamine solution through the at least one secondcompartment and passing into at least one reaction container; passingsaid N-heterocyclic compound of the general formulae (IIIa), (IIIb) or(IIIc) through the at least one third compartment comprising the atleast one cyclization catalyst scavenging matrix and collecting acyclized catalyst free N-heterocyclic compound of the general formulae(IIIa), (IIIb) or (IIIc) in at least one reaction container, whereingeneral formulae (IIIa) is R⁸—CH—CH₂—X—(CR⁴R⁵)_(n)—(CR⁶R⁷)_(m)—NH,general formulae (IIIb) is R⁸R⁹C—CH₂—X—(CR⁴R⁵)_(n)—(CR⁶R⁷)_(m)—NH, andgeneral formulae (IIIc) is R⁸R⁹C—CXR¹⁰—(CR⁴R⁵)_(n)—(CR⁶R⁷)_(m)—NH,wherein R⁴-R⁹ have the above meanings; loading at least one fourthcompartment comprising at least one ion exchange support with thecyclized catalyst free N-heterocyclic compound of the general formulae(IIIa), (IIIb) or (IIIc), washing a loaded ion exchange support with anappropriate solvent system; eluting a N-heterocyclic reaction productfrom the ion exchange support using an appropriate solvent system andcollecting the eluted N-heterocyclic reaction product in at least onereaction container.
 4. The process according to claim 1, wherein thereaction product is eluted from the at least one purifying compartmentafter the cartridge is removed by the user from the apparatus.
 5. Acartridge for the automated chemical synthesis of compounds comprisingat least one N-heterocyclic structure for use in an apparatus for theautomated synthesis of at least one chemical compound, the apparatuscomprising: (a) at least one solvent container for storing solventsystem(s) used for at least one compartment of at least one cartridge,the at least one solvent container comprising at least one solventreservoir, the at least one solvent reservoir having an inlet and anoutlet, (b) at least one reaction container for providing compound(s) tobe fed into at least one of the compartments of the at least onecartridge and/or collecting reaction product(s) from at least one of thecompartments of the at least one cartridge, the at least one reactioncontainer having an inlet and an outlet; (c) at least one first valvefor selecting a liquid source from the at least one solvent reservoir orthe at least one reaction container, the at least one first valve havingan inlet connected to the outlet of the at least one solvent reservoirand the outlet of the at least one reaction container, and an outletconnected to a pump inlet; (d) at least one pump comprising a first pumpcomprising the pump inlet for receiving liquid from the outlet of thefirst valve and a pump outlet connected to an inlet of at least onesecond valve for directing the liquid received from the at least onefirst valve to the at least one second valve either directly or throughoptional pump(s) of the at least one pump; (e) the at least one secondvalve for directing the liquid received from the at least one pump to aninlet of at least one compartment of the at least one cartridge or theinlet of the at least one reaction container, the at least one secondvalve having the inlet for receiving the liquid from the at least onepump, and an outlet connected to the inlet of the at least onecompartment of the at least one cartridge and the inlet of the at leastone reaction container, the cartridge comprising: at least one firstcompartment for providing at least one first reagent for the chemicalsynthesis of the at least one compound, the at least one firstcompartment having the inlet connected to the outlet of the at least onesecond valve, and an outlet connected to the at least one reactioncontainer for passing a formed substrate-reagent intermediate productinto the at least one reaction container, the at least one firstcompartment comprising the first reagent as at least one on animmobilized Sn-containing reagent (SnAP reagent) of the general formulae(Ia)R¹R²R³Sn—CH₂—X—(CR⁴R⁵)_(n)—(CR⁶R⁷)_(m)—N═Y-carrier or of the generalformulae (Ib)R¹R²R³Sn—CHXR¹⁰—(CR⁴R⁵)_(n)—(CR⁶R⁷)_(m)—N═Y-carrier wherein R¹, R², R³,R¹⁰ are selected from a group comprising alkyl, wherein R¹, R², R³ canbe the same or different; X is selected from a group comprising O,protected N, S; R⁴, R⁵, R⁶, R⁷ are selected from a group comprising H,alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, wherein R⁴, R⁵, R⁶, R⁷can be the same or different; and/or at least one of R⁴, R⁵ and at leastone of R⁶, R⁷ together form an alkyl or (hetero-) aryl ring system, orat least two of R⁴ and R⁵ or at least two of R⁶, R⁷ together form aalkyl or aryl spirocyclic ring system, which can be interrupted by oneor multiple oxygen atoms, sulphur atoms, substituted and/orunsubstituted nitrogen atoms and/or by one or multiple groups of thetype —C(O)O—, —OC(O)—, —C(O)—, —NHC(O)O—, —OC(O)NH— and/or —OC(O)O, n,m=1-6, Y═P(R¹¹)₂, wherein R¹¹ can be at least one alkyl or aryl, carrieris a polymer or a silica compound, wherein the at least one of aSn-containing reagent of general formulae (Ia) or (Ib) is able to reactwith at least one aldehyde of the general formulae (IIa)R⁸—CHO or at least one ketone of the general formulae (IIb)R⁸R⁹CO wherein R⁸ and R⁹ are selected from a group comprising alkyl,alkenyl, cycloalkyl, cycloalkenyl, —COOR¹² (R¹² being alkyl), aryl,heteroaryl, which are in each case non-substituted or substituted; orwhere R⁸ and R⁹ are joined to form an alkyl ring system, which can beinterrupted by one or multiple oxygen atoms, sulphur atoms, substitutedand/or unsubstituted nitrogen atoms and/or by one or multiple groups ofthe type —C(O)O—, —OC(O)—, —C(O)—, —NHC(O)O—, —OC(O)NH— and/or —OC(O)O,to form at least one imine or ketimine; at least one second compartmentfor providing at least one second reagent for the chemical synthesis ofthe at least one compound, the at least one second compartment having aninlet for receiving the substrate-reagent intermediate product from theoutlet of the at least one reaction container, and an outlet connectedto the inlet of the at least one reaction container for passing theformed reaction product into the at least one reaction container, the atleast one second compartment comprising the second reagent as at leastone catalyst for cyclization of the at least one imine or the at leastone ketimine leaving the at least one first compartment to at least oneN-heterocyclic compound of the general formulae (IIIa)R⁸—CH—CH₂—X—(CR⁴R⁵)_(n)—(CR⁶R⁷)_(m)—NH or of the general formulae (IIIb)R⁸R⁹C—CH₂—X—(CR⁴R⁵)_(n)—(CR⁶R⁷)_(m)—NH or of the general structure(IIIc)R⁸R⁹C—CXR¹⁰—(CR⁴R⁵)_(n)—(CR⁶R⁷)_(m)—NH wherein R⁴-R⁹ have the abovemeanings wherein the at least one cyclization catalyst is selected froma group comprising a copper salt or a Scandium salt, at least one thirdcompartment for purifying the at least one synthesized compound, the atleast one third compartment having an inlet connected to the outlet ofthe reaction container for receiving the formed reaction product fromthe outlet of the first reaction container, and an outlet connected tothe inlet of the at least one reaction container for passing thepurified product into the at least one reaction container, the at leastone third compartment comprising at least one scavenging matrix forremoving the at least one cyclization catalyst from the reaction mixturecomprising the N-heterocyclic compound leaving the at least one secondcompartment B, and at least one fourth compartment comprising at leastone ion exchange support for purifying the N-heterocyclic reactionproduct.
 6. The cartridge according claim 5, wherein the at least onefirst compartment comprises at least one on a polymer immobilizedSn-containing reagent of the general structure (Ia)R¹R²R³Sn—CH₂—X—(CR⁴R⁵)_(n)—(CR⁶R⁷)_(m)—N═Y-polymer or of the generalstructure (Ib)R¹R²R³Sn—CHXR¹⁰—(CR⁴R⁵)_(n)—(CR⁶R⁷)_(m)—N═Y-polymer wherein R¹, R², R³,R¹⁰ are selected from a group comprising C₁-C₁₀ alkyl, wherein R¹, R²,R³ can be the same or different; X is selected from a group comprisingO, protected N, S; R⁴, R⁵, R⁶, R⁷ are selected from a group comprisingH, C₁-C₂₀ alkyl, C₅-C₁₀ cycloalkyl, C₂-C₂₀ alkenyl, C₅-C₁₀ cycloalkenyl,C₆-C₁₂ aryl, wherein R⁴, R⁵, R⁶, R⁷ can be the same or different; and/orat least one of R⁴, R⁵ and at least one of R⁶, R⁷ together form a 5 to12 membered alkyl or aryl ring system, or at least two of R⁴ and R⁵ orat least two of R⁶, R⁷ together form a 4-7 membered alkyl or arylspirocyclic ring systems; which can be interrupted by one or multipleoxygen atoms, sulphur atoms, substituted and/or unsubstituted nitrogenatoms and/or by one or multiple groups of the type —C(O)O—, —OC(O)—,—C(O)—, —NHC(O)O—, —OC(O)NH— and/or —OC(O)O, n, m=1, 2, 3, 4, 5,Y═P(R¹¹)₂, wherein R¹¹ is aryl; carrier is a polymer, wherein the atleast of Sn-containing reagent of general formulae (Ia) or (Ib) is ableto react with at least one aldehyde of the general formulae (IIa)R⁸—CHO or at least one ketone of the general formulae (IIb)R⁸R⁹CO wherein R⁸ and R⁹ are selected from a group comprising C₁-C₂₀alkyl, C₂-C₂₀ alkenyl, C₅-C₁₀ cycloalkyl, C₅-C₁₀ cycloalkenyl, —COOR¹²(R¹² being C₁-C₁₀ alkyl), C₆-C₁₂ aryl, or where R⁸ and R⁹ are joined toform an C₅-C₁₂ alkyl or C₆-C₁₂ aryl ring system, in particular a C₆ arylring which can be interrupted by one or multiple oxygen atoms, sulphuratoms, substituted and/or unsubstituted nitrogen atoms and/or by one ormultiple groups of the type —C(O)O—, —OC(O)—, —C(O)—, —NHC(O)O—,—OC(O)NH— and/or —OC(O)O, to form at least one imine or ketimine.
 7. Thecartridge according to claim 5, wherein the at least one secondcompartment comprises at least one catalyst selected from a groupcomprising Cu(Z)₂ or Sc(Z)₃ wherein Z is selected from a groupcontaining OTf, Cl, Br, SO₄ ²⁻.
 8. The cartridge according to claim 5,wherein the at least one third compartment comprises at least onescavenging matrix for removing the at least one cyclization catalystselected from a group comprising polymer-supported thiourea,polymer-supported trisamine and silica-supported trisamine, and the atleast one fourth compartment comprises an ion exchange resin or a silicasupported ion exchange for purifying the N-heterocyclic reactionproduct.